The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of Class I and II HDACs as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as non-selective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of a first non-selective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.

The complex TpW(NO)(PMe 3 )(η 2 -benzene) was treated with an excess of phenol to generate TpW-(NO)(PMe 3 )(η 2 -2H-phenol) as a mixture of two stereoisomers. This complex in the presence of base undergoes reactions with several common classes of electrophiles, including benzaldehyde, alkyl iodides, and Michael acceptors, to form new C-C bonds. Methyl and ethyl iodide react at C2 to form 2-alkyl-2H-phenol complexes, whereas the Michael acceptors react at C4 to give 4-alkyl-4H-phenol complexes. In both cases, the electrophile adds to the complexed phenol stereoselectively, anti to the metal. In the case of benzaldehyde, an aldol condensation reaction occurs at C2 to form a rare example of a thermally stable o-quinone methide complex. Crystal structures of the 2-ethyl-2H-phenol and the phenyl o-quinone methide complexes are included.